Otosclerosis is a dystrophic disorder of the otic capsule and ossicles; above all it affects the stapes in the entrance of oval window (footplate and annular ligament). It causes stapes ipomobility and fixation and it can result in conductive or mixed hearing loss.
It is a relatively frequent disorder: the overall prevalence of histologic otosclerosis is about 10%. Approximately 10% of these are affected clinically; so, the overall prevalence of noticeable hearing loss secondary to otosclerosis approximately 1% in the population.
RACE: This disease is more common in Caucasians than in other races. 10-20% of Caucasians have histologic otosclerosis while only 1% of African Americans are affected. Overall, clinical disease is present in 1% of Caucasians, 0.5% of Asians, 0.1% of African Americans and 0% of Native Americans.
SEX: The female-to-male ratio is about 1:1 for asymptomatic histological lesions, but many studies revealed that hearing loss secondary to otosclerosis is more common in women (2x risk) than in men; additionally, women have more often a bilateral disorder. This may be explained by the fact that pregnancy seems to accelerate the progression of otosclerosis, but there’s no evidence yet.
AGE: The incidence of otosclerosis increases with age. The most common age group presenting with hearing loss from otosclerosis is 15-45 years. Children presenting with otosclerosis most often have a positive family history and progressive hearing loss.
Otosclerosis is an osseous dyscrasia, limited to the temporal bone, and characterized by resorption and formation of new bone in the area of the ossicles and otic capsule.
The most common site of involvement in otosclerosis is the anterior oval. When both the anterior and posterior ends of the footplate are involved it is termed “bipolar” involvement or fixation (if the footplate is immobile). When the entire footplate and annular ligament are involved it is known as an obliterated footplate or obliterative otosclerosis. The round window is involved in approximately 30% to 50% of cases but the niche is rarely completed obliterated.
When otosclerosis spreads to the inner ear, a sensorineural hearing impairment (hair cell loss) results due to interference with the inner ear function. This hearing impairment is called cochlear otosclerosis, and once it develops, it is permanent. Bone resorbing cells called osteoclasts in the ear cause a release of enzymes, which damage inner ear hair cells.
: the appearance of otosclerosis differs depending on the stage of the disease. In fact, there are two main phases we can describe:
- “Otospongiosis” or spongiotic phase, characterized by multiple active cell groups including osteocytes, osteoblasts, and histiocytes. It develops a spongy appearance because of vascular dilation secondary to osteocyte resorption of bone surrounding blood vessels. This can be seen grossly as red hue behind the tympanic membrane termed “Schwartze's sign” (described by Schwartze in 1873). Microscopically, a focus of active otosclerosis reveals finger projections of disorganized bone, rich in osteocytes particularly at the leading edge. In the center of the focus, multinucleated osteocytes are often present.
- Sclerotic phase, in which dense sclerotic bone forms in the areas of previous resorption.
many studies suggest the presence of activated osteoclasts
in otosclerotic lesions. These cells begin bone remodeling and they “trigger” the pathogenic way.TGFbeta Histiocytic activity in the otosclerotic bone
a. Horizontal slice of temporal bone with otosclerosis fixing the stapes bone.
b. Otosclerosis involving the wall of the cochlea.
c. Normal bone
|Thus, it begins with bone resorption, followed by fibrosis and vascularization of the temporal bone in the immediate vicinity of the oval window, in time replaced by dense new bone anchoring the footplate of the stapes. In most instances, the process is slowly progressive over the span of decades, leading eventually to marked hearing loss.|
The inciting event that initiates the onset this disease is unknown. Many theories have been proposed such as hereditary, endocrine, metabolic, infectious, vascular, and most recently, autoimmune, however, none have be proven. Hormonal factors have been suggested to play a role in otosclerosis based on the observation that pregnancy sometimes accelerates the progression of the disease. In 1912 Siebenmann came up with the term labyrinthine otosclerosis referring to foci of otosclerosis involving the otic capsule of the cochlea and labyrinth. He proposed that labyrinthine otosclerosis could result in SNHL (SensoNeurinal Hearing Loss). To this day, this is a debated topic. Proposed theories of how SNHL may result from otosclerosis include liberation of toxic metabolites into the inner ear, decreased blood supply, and direct extension of the otosclerotic focus into the inner ear resulting in changes in electrolyte concentrations and alterations of the biomechanics of the basilar membrane.
- GENETIC FACTORS: there is positive family history in 50% of cases (autosomal dominant transmission low-penetrance)
Localization of a gene for otosclerosis to chromosome 15q25-q26
Single-nucleotide polymorphisms in the COL1A1 regulatory regions are associated with otosclerosis.
Detection of rare nonsynonymous variants in TGFB1 in otosclerosis patients.
In fact, TGFbeta1 is involved in bone remodeling:
Meccanismi di rigenerazione del tessuto osseo :
“Alla formazione di tessuto osseo, nelle sedi di sintesi partecipano: le cellule osteoprogenitrici (fibroblasti, osteoblasti e condrociti), un’impalcatura o matrice osteoconduttiva, molecole di segnale rappresentate dai fattori di crescita osteoinduttivi (PDGF, TGF-beta, IGF I e II di derivazione piastrinica) e proteine ad attività morfogenetica (BPMS). Recentemente, è stato possibile dimostrare che le BPMS sono peptidi osteoinduttivi di derivazione piastrinica appartenenti al gruppo delle TGF-beta responsabili dell'organogenesi extracellulare, nonché dei processi di generazione e rigenerazione dell'osso.
Schematicamente, è stato ipotizzato che nel sito di lesione osseo ci sia un rilascio iniziale di PDGF, TGF-beta e IGF I e II per effetto della degranulazione delle piastrine presenti in loco. Il PDGF stimola la mitosi delle cellule staminali midollari presenti nell’ osso mentre dall’altro, in virtù dell’effetto angiogenetico, determina la formazione dei nuovi capillari nelle sedi di lesione. Contemporaneamente si assiste ad una proliferazione di fibroblasti e di proosteoblasti per effetto del TGF-beta. Successivamente lo stesso TGF-beta induce la differenziazione dei proosteoblasti verso le forme più mature. L’attività del TGF-beta si esplica anche su queste ultime (osteoblasti) che vengono stimolati a produrre matrice ossea, e sui fibroblasti che depositano la matrice di collagene destinata a sostenere la crescita vasale.”
TGFbeta come fattore differenziativo per gli osteoclasti :
“Caratterizzazione dell’effetto del TGF beta 1 sulla differenziazione di cellule preosteoclastiche in cellule osteoclastiche mature. A tale scopo e’ stata utilizzata una linea cellulare denominata FLG 29.1 con caratteristiche preosteoclastiche e che e’ in grado di differenziarsi in presenza di estere del forbolo (TPA) in cellule osteoclastiche mature. Le cellule indifferenziate mostrano recettori per il TGF beta 1 ed in queste cellule basse dosi di TGF beta 1 sono in grado di indurre la adesione cellulare e la risposta alla calcitonina (in termini di accumulo di cAMP) e di inibire la crescita cellulare, tutti parametri tipici della differenziazione cellulare verso il fenotipo osteoclastico. Le cellule indifferenziate sono anche in grado di produrre quantita’ misurabili di TGF beta 1 (come evidenziato da un metodo ELISA e da analisi di Northern blotting) unicamente in forma latente ed il trattamento con TPA potenzia enormemente questa produzione senza influenzare la latenza del TGF beta 1. E’ interessante notare come dopo trattamento con TPA le cellule FLG 29.1 non siano più in grado di esprimere il recettore estrogenico evidenziato da studi di binding e questo probabilmente perche’ il TGF beta 1 prodotto dalle cellule differenziate va ad occupare i siti recettoriali disponibili saturandoli.”
Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss.
- VIRAL FACTORS:Paramyxoviral structures have been identified by electron microscopy and the expression of measles virus antigen has been observed by immunohistochemistry in active otosclerotic tissue. By use of the polymerase chain reaction, measles virus related sequences have been detected in otosclerotic bone tissue but not in control specimens. Probably it provokes a local immune response within the inner ear and this may be the cause of osteoclasts’ activation.
Otosclerosis and measles virus - association or causation?
ORL J Otorhinolaryngol Relat Spec. 2008;70(1):63-9; discussion 69-70. Epub 2008 Feb 1.
Niedermeyer HP, Arnold W.
This study demonstrates that measles virus is a triggering factor, because of “highly significant decrease in otosclerosis among the population vaccinated against the MV.”
Antimeasles immunoglobulin G and virus-neutralizing activity in sera of patients with otosclerosis.
Viruses, especially herpes viruses like EBV, CMV and HHV6, make proteins that mimic IL-10. So the immune system shifts from the Th1 mode that attacks viruses to the Th2 mode that does not. The virus increases its chances of survival by diverting the immune system. It is now thought that many, if not most, pathogens have this ability.
Measles Virus Infection in Adults Induces Production of IL-10 and Is Associated with Increased CD4+CD25+ Regulatory T Cells1
a) Recent studies indicate that CD4+CD25+ regulatory T (TReg) cells and non-T cells that express interleukin-10 (IL-10) (possibly macrophages and/or dendritic cells) cooperate to generate polarized T helper 2 (TH2)-cell responses. Transforming growth factor-beta1 (TGF-beta1)-producing TReg cells might also promote the development of IL-10-producing TReg cells74. IL-10 can directly inhibit collagen synthesis by fibroblasts. IL-10 also inhibits interferon-gamma (IFN-gamma) production by TH1 cells, while promoting the development of a polarized but controlled TH2 response2. In this setting, IL-13 induces collagen deposition by fibroblasts; however, it also induces expression of its decoy receptor IL-13 receptor-alpha2 (IL-13Ralpha2), which ultimately attenuates the response. Recent evidence indicates that fibroblasts are an important source of IL-13Ralpha2. Therefore, both IL-10 produced by TReg cells and the IL-13Ralpha2 might cooperate to control fibrosis during polarized TH2 responses.
b)When a highly polarized TH1 response is generated, little IL-13 is produced. Consequently, fibrosis is minimal and decoy-receptor expression remains low.
c) When a mixed TH1/TH2 response develops, IFN-gamma might decrease production of the IL-13 decoy receptor and upregulate IL-13 effector function. In this case, although IL-13 concentrations might slightly decrease or remain unchanged, more IL-13 is free to bind the signalling receptor. This could explain the unusual tendency of mixed responses to trigger severe tissue pathology.
Expression of collagens in the otosclerotic bone.
- VASCULAR FACTORS:a blood flow reduction could be the cause of SensoNeurinal Hearing Loss, because a reduction of ATP production means worse ATPases function and alteration of endocochlear potential (EP). In fact, it is highly dependent on metabolism and ion-transport. In the event of systemic anoxia or treatment with ion-transport inhibitors, such as ouabain, ethacrynic acid, or furosemide, the EP rapidly falls and becomes negative within a matter of minutes.
Intervention of spiral ligament fibrocytes in the metabolic regulation of the inner ear
Gastric type H+,K+-ATPase in the cochlear lateral wall is critically involved in formation of the endocochlear potential.
Histopathology of the Spiral Ligament in Cochlear Otosclerosis: Its Role in Ion Transport and Pathogenesis of Sensorineural Hearing Loss
“[…]Some temporal bones with cochlear otosclerosis have shown decreased staining for Na,K-ATPase, CAII, and connexin 26 channels, when compared to normal cochleae. This study demonstrated that spiral ligament hyalinization is associated with and may result in both stria vascularis atrophy and sensorineural hearing loss. This data indicates that spiral ligament structure and function are essential for stria vascularis survival. In addition, the audiometric data presented here suggest that the spiral ligament is necessary for stria vascularis function as well since hyalinized spiral ligament is associated with stria vascularis atrophy and, in turn, senorineural hearing loss. Loss of ion transport channel expression may result from cochlear involvement with otosclerosis and may contribute to spiral ligament and stria vascularis dysfunction.”
Spiral ligament and stria vascularis changes in cochlear otosclerosis: effect on hearing level.
Ruolo del progesterone sui linfociti
High progesterone levels in pregnancy have an immunological role: it let lymphocytes release PIBF (progesterone induced blocking factor, that impairs NK function and that helps to maintain pregnancy) and Th2 cytokines (there's a Th1 and Th2 shift)
Progesterone binding to the alpha1-subunit of the Na/K-ATPase on the cell surface: insights from computational modeling.
Some studies reveal the presence of high levels of alkaline phosphatase in otosclerotic stapes
Composition of the otosclerotic stapes: electron microprobe analyses.
- AUTOIMMUNE RESPONSE:
Detection of humoral immune response to inner ear proteins in patients with sensorineural hearing loss
Antibodies to the minor cartilage collagen type IX in otosclerosis.
Cartilage-specific autoimmunity in otosclerosis
Hearing loss is the most frequent symptom of otosclerosis. The loss may appear very gradually. Many people with otosclerosis first notice that they cannot hear low-pitched sounds or that they can no longer hear a whisper.
In addition to hearing loss, some people with otosclerosis may experience dizziness, balance problems, or tinnitus (a sensation of ringing, roaring, buzzing, or hissing in the ears or head).
Approximately 25% of patients with otosclerosis may present otosclerotic inner ear syndrome, with paroxysmal vertigo or, most frequently, mild disequilibrium (D.d. Menière syndrome).
The audiogram, particularly with respect to pure tones, tympanometry, and acoustic reflexes, is the most important objective test in diagnosing and planning treatment for patients with otosclerosis.
- Otoscopy:normal findings
- Weber test:it should lateralize to the ear with a greater degree of conducting hearing loss
- Rinne test:negative (because it is a transmission hypoacusia)
The first affect of early otosclerosis on pure tones is a decrease in air conduction in the low frequency, especially below 1000 Hz. The rising air line seen in these patients is referred to as a “stiffness tilt” and is called such because it is caused by decreased compliance secondary to stapes fixation. As the disease progresses, the air line flattens. This occurs because the otosclerotic focus has a mass affect on the entire system in addition to decreasing its compliance. Further progression of otosclerosis to involve the cochlea may result in increased bone conduction thresholds. Usually high frequencies are affected first because the disease focus is usually adjacent to the basal turn of the cochlea. More isolated cochlear otosclerosis may sometimes result in a mixed hearing loss.
The Carhart notch is the hallmark audiologic sign of otosclerosis. It is characterized by a decreased in the bone conduction thresholds of approximately 5 dB at 500 Hz, 10 dB at 1000 Hz, 15 dB at 2000 Hz, and 5 dB at 4000 Hz. It results from a mechanical artifact and is not a true representation of the cochlear reserve. It is postulated that this phenomenon occurs because stapes fixation disrupts the normal ossicular resonance and that the normal compressional mode of bone conduction is disturbed because of relative perilymph immobility caused by stapes fixation. These theories are supported by the fact that Carhart’s notch disappears after stapedectomy.
The vast majority of cases of otosclerosis are associated with conductive or mixed hearing loss.
Because middle ear air pressure is not affected by otosclerosis, the peak of the tympanogram is always in the normal range along the x-axis. Compliance of the system, however, is reduced as otosclerosis progresses resulting in depression of the height of the peak.
A low peak in the normal middle ear pressure range is called a type As (s-stiffness curve) tympanogram and is characteristic of advanced otosclerosis but more commonly, malleus fixation.
- Acoustic reflexes:
The first sign of early otosclerosis (even before any conductive hearing loss is detected) is a diphasic reflex pattern (ie increase compliance at the onset and cessation of the sound stimulus= “ON-OFF effect”). Probably it results from inherent elasticity in the otosclerotic anterior footplate and crura allowing the non-affected posterior footplate to move with stapedius contraction and relaxation. As stapes fixation progresses, the acoustic reflex amplitudes are reduced, followed by elevation of ipsilateral, then contralateral thresholds, and finally, disappearance of the reflexes altogether.
ABR would be abnormal with otosclerosis, and it would be abnormal for a vestibular schwanomma/acoustic neuroma as well. If the pathology were otosclerosis, the interpeak latencies would be normal, but the waves I, III and V would be delayed. If it were the vestibular schwanomma, you may have one or two delayed waves and possibly a waveform morphology breakdown at a fast click rate.
It is controversial whether imaging studies are needed, beyond the physical exam, tuning forks, and audiogram, in diagnosing and managing patients with otosclerosis. Those in favor of High-resolution computed tomography (HRCT) scanning of the temporal bone in these patients site a number of advantages.
HRCT can characterize the extent of the otosclerotic focus at the oval window and can be used when the clinical diagnosis is in doubt (patients with profound mixed hearing loss).
HRCT scanning of the temporal bone should be taken in the axial and coronal oblique planes.
Foci of early or active otosclerosis or otospongiosis are poorly calcified and they appear as hypodense areas. As re-ossification occurs the oval window appears smaller or obliterated by bone.
In cochlear otosclerosis, active foci give the appearance of a ring around the cochlea. This is termed “double ring effect” or the “halo” sign.
Otosclerosis: incidence of positive findings on high-resolution computed tomography and their correlation to audiological test data.
- Paget’s disease:
Although other physical findings will likely be present to distinguish them from one another, it is worth mentioning the unique CT findings of Paget’s disease in the temporal bone. This disease is characterized by initial bone resorption followed by diffuse bony hypertrophy. Most commonly the petrous bone is affected first in which the internal auditory canal is usually the first structure involved followed by the cochlea and vestibular system. On CT there is a typical washed-out appearance of both temporal bones due to severe demineralization. As remodeling of bone occurs the entire temporal bone becomes thickened. The stapes is often involved and less commonly the incus and malleus.
- Osteogenesis imperfecta:
CT findings in osteogenesis imperfecta often reveal an abnormally thin calvarium. Active otosclerotic foci in the temporal bone usually involve the entire otic capsule.
Otosclerosis may be slowly progressive, not requiring treatment until the extent of the hearing loss is significant. There is no medical treatment for the conductive hearing loss. Medication such as sodium fluoride can be used when the inner ear type (e.g. cochlear otosclerosis) is involved, not to return the sensorineural hearing loss back to normal, but to slow or prevent further hair cell loss. This medication is only given to those patients who have evidence of having hair cell loss, as a result of involvement of the cochlea. Sodium fluoride is a substance that appears to increase the hardening of the bone around the cochlea and inhibit osteoclast activity. In addition some antioxidants may play a role in decreasing the osteoclast activity, providing some benefit. Common antioxidants are Flavonoids (often referred to as the P vitamins). There are 4 forms including Proanthocyanidins, Quercetin (most active of the flavonoids), Citrus bioflavanoids, and Green Tea Polyphenols.
Increased activity of the diastrophic dysplasia sulfate transporter in otosclerosis and its inhibition by sodium fluoride.
- ricerca pubmed: "flavonoid quercetin bone"
Studies reveal also the potential role of Bisphosphonate on bone remodeling in otosclerosis
Medical treatment of otosclerosis: rationale for use of bisphosphonates.
Hearing aids represent a non-surgical option for treatment when the hearing loss is significant. Hearing aids are effective for both the stapedial otosclerosis and/or cochlear otosclerosis conditions.
In the majority of cases, surgery is an option for treatment of otosclerosis. Use of a prosthesis or laser can provide improved movement of the stapes bone.
- A stapedectomy involves the entire removal of the stapes and its replacement with a prosthesis.
- Another option is a small fenestra stapedotomy, where only a portion of the stapes bone is removed and a small opening in made in the bottom (footplate) of the stapes bone allowing a small prosthesis to move the fluid in the inner ear.
- A third option is the laser stapedotomy operation, which makes an opening in the bone to allow for fluid movement, and is more often recommended for patients with stapedial otosclerosis, who are candidates for surgery.
This operation is performed under local or general anesthesia as an outpatient surgery. Recovery is usually quick and hearing is permanently restored in over 90 percent of these operations. For the stapes operation to be successful in restoring hearing in otosclerosis, the bone conduction (e.g. a function of hair cell function) must be able to receive and transmit sound to the brain adequately. Therefore, the degree of sensorineural hearing loss will be important in determining the expected results of the surgery. It is important to discuss the risks and possible complications of the procedure, as well as the expected benefits. In the majority of cases the hearing is improved. In rare cases, surgery can worsen the hearing loss.